本文選題：肝細(xì)胞肝癌 + 遺傳易感性�。� 參考：《安徽醫(yī)科大學(xué)》2017年博士論文

【摘要】：背景肝細(xì)胞肝癌(hepatocellular carcinoma,HCC)是世界上第五大致命的惡性腫瘤,惡性程度高、進(jìn)展快、預(yù)后差,社會負(fù)擔(dān)沉重。亞洲是HCC重災(zāi)區(qū),而我國HCC的發(fā)病率和死亡率也呈上升趨勢。盡管目前HCC基礎(chǔ)和臨床研究取得諸多成果,外科手術(shù)、介入治療、射頻消融等治療方法使很多患者受益,但是HCC起病隱匿、早期癥狀不明顯,晚期HCC十分常見且呈增加趨勢,這些患者多伴遠(yuǎn)處轉(zhuǎn)移,預(yù)后極差。同時,手術(shù)后復(fù)發(fā)也是HCC治療的巨大挑戰(zhàn)。因此,尋找更具潛力的生物標(biāo)志物和治療靶標(biāo)將有助于HCC早期診斷和有效治療。HCC是炎癥相關(guān)性癌癥的典型代表之一,肝臟中慢性炎癥狀態(tài)(以乙型肝炎病毒(Hepatitis virus B,HBV)感染常見)通過持續(xù)表達(dá)細(xì)胞因子和募集免疫細(xì)胞到肝臟,從而在腫瘤發(fā)生與發(fā)展中發(fā)揮作用。眾所周知,遺傳因素在HCC發(fā)生與發(fā)展中發(fā)揮重要作用,其中單核苷酸多態(tài)性(single nucleotide polymorphism,SNP)是基因多態(tài)性的主要形式之一,在人群中頻率大于1%。SNP可以很好反映不同個體間的遺傳差異,還可能調(diào)控基因表達(dá),進(jìn)而影響不同個體對某種疾病的易感性。SNP已被廣泛應(yīng)用于人類各種疾病的研究中,其中腫瘤相關(guān)SNP在個體對癌癥易感性中扮演重要角色。巨噬細(xì)胞是腫瘤中浸潤最多的免疫細(xì)胞,腫瘤相關(guān)巨噬細(xì)胞(tumor-associated macrophages,TAMs)是實(shí)體腫瘤中免疫浸潤物的主要成分。TAMs在腫瘤發(fā)生、發(fā)展及預(yù)后中發(fā)揮的作用已被廣泛研究。巨噬細(xì)胞一般被分為經(jīng)典活化型(M1型巨噬細(xì)胞)和替代活化型(M2型巨噬細(xì)胞),一般認(rèn)為TAMs屬于M2型巨噬細(xì)胞,具有類似M2的標(biāo)志物及促癌功能;但也有研究表明TAMs可以從M2樣巨噬細(xì)胞向M1樣細(xì)胞逆轉(zhuǎn),具有可逆性。TAMs這種復(fù)雜的生物學(xué)特點(diǎn)給臨床研究和實(shí)踐帶來巨大挑戰(zhàn)。然而,目前TAMs在肝癌發(fā)生發(fā)展中的角色仍未被完全闡明。CD68是重要的巨噬細(xì)胞特異性膜蛋白,也是泛巨噬細(xì)胞可靠的標(biāo)志物。除了多種組織中定居的巨噬細(xì)胞,CD68還表達(dá)于腫瘤浸潤巨噬細(xì)胞。CD206,又稱巨噬細(xì)胞甘露糖受體(macrophage mannose receptor,MMR)或甘露糖受體C1型(MRC1)是一種具有噬菌和內(nèi)吞作用的模式識別受體,主要表達(dá)于大部分巨噬細(xì)胞和樹突細(xì)胞亞群,通常被用來鑒定M2型巨噬細(xì)胞。目前,CD68和CD206在人類疾病中的結(jié)構(gòu)與功能已被廣泛關(guān)注,但是有關(guān)CD68和CD206的基因多態(tài)性與人類HCC的易感性及預(yù)后是否存在關(guān)聯(lián)、兩者在HCC患者血清中表達(dá)水平尚未見文獻(xiàn)報(bào)道。本研究從DNA、組織學(xué)、血清學(xué)三個不同層面比較系統(tǒng)研究了CD68和CD206在HCC中的表達(dá)及意義。目的本課題分為三個部分進(jìn)行研究。第一部分:探究CD68和CD206三個位點(diǎn)(CD68 rs9901675、CD68rs9901673、CD206 rs941)多態(tài)性及其與HCC發(fā)病風(fēng)險(xiǎn)及患者預(yù)后的關(guān)聯(lián)性,以期為HCC發(fā)病機(jī)制的研究提供新的切入點(diǎn)。第二部分:探討CD68陽性巨噬細(xì)胞和CD206陽性巨噬細(xì)胞的數(shù)量和分布在HCC癌組織和癌旁組織中有無差異,評估其預(yù)后價(jià)值。第三部分:初步探討HCC患者和健康對照者血清中可溶性CD68(a soluble form of s CD68,s CD68)和可溶性CD206(a soluble form of s CD206,s CD206)表達(dá)水平及其對HCC的診斷及預(yù)后意義,為HCC個體化臨床診治和長期隨訪管理提供有效的理論依據(jù)。方法第一部分:采用病例對照研究,連續(xù)收集符合條件的原發(fā)性HCC患者311例和健康體檢者415名,采集研究對象的一般情況、臨床及預(yù)后生存資料,同時收集全血標(biāo)本、提取基因組脫氧核糖核酸(deoxyribonucleic acid,DNA),檢測CD68和CD206基因三個位點(diǎn)的多態(tài)性,分析其與HCC發(fā)病風(fēng)險(xiǎn)、臨床表型以及預(yù)后的關(guān)系。第二部分:選擇268例行肝切除手術(shù)HCC患者進(jìn)行回顧性研究。使用免疫組化方法檢測HCC癌組織和癌旁組織中CD68陽性巨噬細(xì)胞和CD206陽性巨噬細(xì)胞,分析不同部位表達(dá)差異;采用受試者工作特征曲線(receiver operating characteristics curve ROC)評價(jià)CD68陽性和CD206陽性兩種巨噬細(xì)胞對HCC的診斷價(jià)值;評估兩者與HCC患者總體生存期和無瘤生存期的關(guān)系以及兩者聯(lián)合檢測對HCC預(yù)后價(jià)值。第三部分:從第一部分研究樣本中選取HCC術(shù)前患者123例和HCC術(shù)后患者60例、健康體檢中心健康體檢者60名,采用酶聯(lián)免疫吸附試驗(yàn)(enzyme linked immunosorbent assay,ELISA)檢測血清中s CD68和s CD206水平,分析兩者變化規(guī)律及其與HCC臨床病理特征之間的關(guān)系,初步探討兩者對HCC的診斷價(jià)值及預(yù)后意義。結(jié)果第一部分:311例HCC患者和415名健康對照的SNP分析結(jié)果顯示,CD68rs9901675多態(tài)性與HCC遺傳易感性有關(guān)(OR=0.409,95%可信區(qū)間(confidence interval,CI)為0.206~0.812,P=0.009),該位點(diǎn)三種基因型GG、GA和AA的頻率在HCC病例組為96.46%、3.54%和0%,對照組為92.53%、6.51%和0.96%,經(jīng)調(diào)整性別年齡后差異具有統(tǒng)計(jì)學(xué)意義(P=0.019);但尚未發(fā)現(xiàn)CD68 rs9901673、CD206 rs941兩個SNP位點(diǎn)與HCC易感性存在關(guān)聯(lián)(P均0.05)。生存分析結(jié)果顯示,CD68 rs9901675是HCC術(shù)后復(fù)發(fā)的獨(dú)立預(yù)測因子[HR(95%CI)=8.114(1.103~59.675),P=0.040],但是該位點(diǎn)多態(tài)性與HCC主要臨床特征之間無顯著相關(guān)性(P0.05)。第二部分:(1)免疫組化檢測結(jié)果顯示:(1)CD68陽性和CD206陽性兩種巨噬細(xì)胞在HCC癌旁組織中的表達(dá)量均顯著高于癌組織(P均0.05);(2)不同年齡、不同血清甲胎蛋白(alpha fetoprotein,AFP)水平、是否伴有門脈高壓的HCC患者癌組織中CD68陽性巨噬細(xì)胞表達(dá)量不同(P均0.05);而是否伴門脈高壓或HBV陽性、不同AFP和腫瘤直徑的HCC患者癌旁組織的CD68陽性巨噬細(xì)胞的浸潤密度亦不同(P均0.05);(3)CD206陽性巨噬細(xì)胞在不同性別、Child-Pugh分級患者的癌組織中表達(dá)水平不同(P均0.05),而是否伴有肝硬化、不同血清總膽紅素和TNM(tumor-nodes-metastasis)分期的患者癌旁組織中表達(dá)強(qiáng)度亦不同(P均0.05)。(2)ROC曲線結(jié)果顯示,癌內(nèi)CD68診斷臨界值(cut-off value)設(shè)定為71個/每高倍視野(high-power fields,HPF),曲線下面積(area under curve,AUC)為0.614,95%CI為0.547~0.678,敏感性52.2%,特異性70.7%,對HCC診斷有意義(P=0.003);癌旁CD68最佳臨界值為87個/每高倍視野(high-power fields,HPF),AUC為0.599,95%CI為0.534~0.661,敏感性49.5%%,特異性70.5%,對HCC診斷有意義(P=0.008)。(3)Kaplan-Meier法比較生存曲線顯示,癌內(nèi)組織高表達(dá)CD206的HCC患者預(yù)后差,總體生存期(P=0.014)和無瘤生存期(P=0.003)均短于低表達(dá)組患者;而癌旁組織高表達(dá)CD68的HCC患者總體生存時間(P=0.020)和無瘤生存時間(P=0.018)則更長。Cox回歸分析結(jié)果顯示,癌旁高表達(dá)的CD68陽性巨噬細(xì)胞是HCC患者總體預(yù)后[HR(95%CI)=0.510(0.311~0.837),P=0.008]和術(shù)后復(fù)發(fā)[HR(95%CI)=0.529(0.299~0.935),P=0.028]的保護(hù)性獨(dú)立預(yù)后因子;而癌內(nèi)高表達(dá)的CD206陽性巨噬細(xì)胞則是HCC患者預(yù)后的獨(dú)立危險(xiǎn)因素:總體生存期[HR(95%CI)=1.792,(1.116~2.879),P=0.016]和無瘤生存期[HR(95%CI)=2.222(1.280~3.856),P=0.005]。(4)聯(lián)合分析癌旁CD68陽性腫瘤巨噬細(xì)胞和HBV的結(jié)果顯示,癌旁CD68陽性巨噬細(xì)胞或癌內(nèi)CD206陽性巨噬細(xì)胞與HBV聯(lián)合分析,HCC患者的無瘤生存期差異均具有統(tǒng)計(jì)學(xué)意義(P均0.05),但是聯(lián)合分析CD68陽性巨噬細(xì)胞與HBV對總生存期無明顯影響(P=0.102)。第三部分:(1)HCC患者手術(shù)前和手術(shù)后血清s CD68和s CD206水平均明顯高于正常對照組(P均0.05),但是術(shù)前與術(shù)后血清s CD68和s CD206水平變化不明顯,差異無統(tǒng)計(jì)學(xué)意義(P均0.05)。同時,術(shù)前與術(shù)后s CD68/s CD206、術(shù)前s CD68與s CD206、術(shù)后s CD68和s CD206均存在相關(guān)性(P均0.05)。(2)進(jìn)一步分析發(fā)現(xiàn),兩者與HCC重要臨床特征(HBV、肝硬化、門脈高壓和血清AFP水平)存在密切聯(lián)系(P均0.05)。(3)CD68 rs9901675、CD68 rs9901673、CD206 rs941三個位點(diǎn)的不同基因型的HCC患者血清中s CD68/s CD206水平均無明顯差異(P均0.05)。(4)ROC曲線分析結(jié)果表明,當(dāng)術(shù)前血清s CD206為20.52ng/ml時,可獲得最大的曲線下面積,術(shù)前血清s CD206具有診斷HCC價(jià)值(P=0.032),而術(shù)前血清s CD68則無統(tǒng)計(jì)學(xué)意義(P=0.174)。(5)生存分析結(jié)果顯示,術(shù)后血清高表達(dá)s CD68、伴有門靜脈癌栓、術(shù)前白蛋白降低、堿性磷酸酶升高、總膽紅素升高、伴有淋巴結(jié)轉(zhuǎn)移或遠(yuǎn)處轉(zhuǎn)移的HCC患者總體生存時間較短,差異均具有統(tǒng)計(jì)學(xué)意義(P均0.05),進(jìn)一步Cox回歸分析結(jié)果顯示,術(shù)后血清高表達(dá)s CD68是獨(dú)立預(yù)后危險(xiǎn)因素[HR(95%CI)=8.059(1.007~64.487),P=0.049]。而術(shù)前s CD68和s CD206以及術(shù)后s CD206對HCC患者預(yù)后未見統(tǒng)計(jì)學(xué)意義(P均0.05)。結(jié)論1.CD68 rs9901675多態(tài)性與HCC患病遺傳易感性有關(guān),該位點(diǎn)G等位基因和GG基因型可能是HCC發(fā)病風(fēng)險(xiǎn)因素,也是HCC術(shù)后復(fù)發(fā)的獨(dú)立危險(xiǎn)因子。2.定量分析HCC組織中CD68陽性和CD206陽性巨噬細(xì)胞可以為HCC患者術(shù)后分層管理提供線索,為再馴化HCC微環(huán)境中巨噬細(xì)胞提供新思路新方法。癌旁高表達(dá)的CD68是HCC患者預(yù)后獨(dú)立保護(hù)因子,而癌內(nèi)高表達(dá)的CD206是HCC患者預(yù)后獨(dú)立危險(xiǎn)因素。聯(lián)合分析CD68或CD206陽性腫瘤巨噬細(xì)胞與HBV感染可能進(jìn)一步提高HCC術(shù)后復(fù)發(fā)的預(yù)測能力。3.檢測HCC患者血清s CD68和s CD206水平有助于觀察免疫狀態(tài),術(shù)前血清s CD206水平可作為HCC患者早期診斷潛在標(biāo)志物,而術(shù)后血清s CD68可為HCC術(shù)后患者總體生存期提供預(yù)測,對HCC患者的臨床診斷和預(yù)后評估具有重要臨床價(jià)值。
[Abstract]:Hepatocellular carcinoma (HCC) is the fifth most fatal malignant tumor in the world, with high malignancy, rapid progress, poor prognosis and heavy social burden. Asia is the hit area of HCC, and the incidence and mortality of HCC in China are also on the rise. Although many achievements have been made in the basic and clinical Research of HCC, surgical operations, Treatment, radiofrequency ablation and other treatment methods benefit many patients, but HCC is insidious and early symptoms are not obvious. Late HCC is very common and tends to increase. These patients are often accompanied by distant metastasis, and the prognosis is extremely poor. At the same time, recurrence is also a huge challenge for HCC treatment. Therefore, to find more potential biomarkers and target targets for treatment. It will help HCC early diagnosis and effective treatment of.HCC is one of the typical cases of inflammation related cancer. Chronic inflammatory state in the liver (hepatitis B virus (Hepatitis virus B, HBV) infection is common) through continuous expression of cytokines and recruitment of immune cells to the liver. It is known to play a role in the development and development of cancer. Genetic factors play an important role in the development and development of HCC, in which single nucleotide polymorphisms (single nucleotide polymorphism, SNP) are one of the main forms of genetic polymorphism. The frequency of more than 1%.SNP in the population can reflect the genetic differences among different individuals, and can also regulate gene expression, and then affect a certain number of individuals. The susceptibility to disease.SNP has been widely used in the study of various human diseases, in which tumor related SNP plays an important role in the susceptibility of cancer. Macrophages are the most infiltrating immune cells in tumor, and tumor related macrophages (tumor-associated macrophages, TAMs) are the main immune infiltrates in solid tumors. The role of component.TAMs in the occurrence, development and prognosis of tumor has been widely studied. Macrophages are generally divided into classical activated type (M1 type macrophages) and replacement activation type (M2 type macrophages). Generally, TAMs is considered as a M2 type macrophage, which has a marker of M2 like and a cancer promoting function; but there are also studies that TAMs can be derived from M2 like The reversal of macrophages to M1 like cells, which has the complex biological characteristics of reversible.TAMs, brings great challenges to clinical research and practice. However, the role of TAMs in the development of liver cancer is still not fully elucidated as an important macrophage specific membrane protein and a reliable marker of Pan macrophage. The colonization of macrophages, CD68 also expressed in tumor infiltrating macrophage.CD206, also known as macrophage mannose receptor (macrophage mannose receptor, MMR), or mannose receptor C1 type (MRC1), is a pattern recognition receptor with phagocytic and endocytosis, mainly expressed in most macrophages and dendritic cell subgroups, usually in the form of a subpopulation of macrophages and dendritic cells. It is used to identify M2 type macrophages. Currently, the structure and function of CD68 and CD206 in human diseases have been widely concerned, but there is a correlation between the genetic polymorphisms of CD68 and CD206 and the susceptibility and prognosis of human HCC. The level of expression in the serum of HCC patients has not yet been reported. This study from DNA, histology, serology three The expression and significance of CD68 and CD206 in HCC were studied at different levels. The purpose of this topic was divided into three parts. The first part was to explore the polymorphism of CD68 and CD206 (CD68 rs9901675, CD68rs9901673, CD206 rs941) and its association with HCC risk and prognosis in order to study the pathogenesis of HCC. The second part is to explore the number and distribution of CD68 positive macrophages and CD206 positive macrophages in the HCC and para cancerous tissues, and to evaluate their prognostic value. The third part: the preliminary study of the soluble CD68 in the serum of HCC and healthy controls (a soluble form of s CD68, s) and soluble solids 206 (a soluble form of s CD206, s CD206) expression level and its significance for the diagnosis and prognosis of HCC, providing an effective theoretical basis for the individualized clinical diagnosis and treatment of HCC and long-term follow-up management. Method first part: a case control study was used to collect 311 cases of primary HCC patients and 415 healthy physical examination persons. The general situation, the clinical and prognosis survival data, collection of whole blood samples, deoxyribonucleic acid, DNA, detection of the polymorphism of three loci of CD68 and CD206 gene, analysis of the relationship with the risk of HCC, the clinical phenotype and the prognosis. The second part: select 268 cases of hepatectomy for HCC patients. An immunohistochemical method was used to detect CD68 positive macrophages and CD206 positive macrophages in HCC carcinoma tissue and para cancerous tissue, and the difference of expression in different parts was analyzed. The diagnosis of CD68 positive and CD206 positive two macrophages on HCC was evaluated by the working characteristic curve of receiver operating characteristics curve ROC. The relationship between the total survival time and the tumor free life period of HCC patients and the value of the combined detection of HCC were evaluated. The third part: from the first part of the study, 123 cases of HCC patients and 60 patients after HCC, 60 healthy physical examination centers in the health check-up center were selected, and the enzyme linked immunosorbent assay (enzyme linked IM) was used. Munosorbent assay, ELISA) detected the level of s CD68 and s CD206 in serum, analyzed the relationship between the two changes and the clinicopathological features of HCC, and preliminarily discussed the diagnostic value and prognostic significance of both of them. Results the first part: the SNP analysis of 311 cases of HCC and 415 healthy controls showed that CD68rs9901675 polymorphism was associated with the remains. The OR=0.409,95% confidence interval (confidence interval, CI) was 0.206~0.812, P=0.009). The frequency of three genotypes of GG, GA and AA in the loci were 96.46%, 3.54% and 0% in HCC cases, and 92.53%, 6.51% and 0.96% in the control group. The difference was statistically significant after the adjustment of sex age (P=0.019). The two SNP loci of rs941 were associated with HCC susceptibility (P 0.05). Survival analysis showed that CD68 rs9901675 was an independent predictor of recurrence of HCC, [HR (95%CI) =8.114 (1.103~59.675), P=0.040], but there was no significant correlation between the polymorphism of the loci and the main clinical features. (1) (1) immunohistochemical detection results. (1) the expression of CD68 positive and CD206 positive macrophages in HCC para cancer tissues was significantly higher than that of cancer tissue (P 0.05); (2) the levels of alpha fetoprotein (AFP) in different ages, different serum alpha fetoprotein (alpha fetoprotein, AFP), and the expression of CD68 positive macrophages in the cancerous tissues of HCC patients with portal hypertension (P 0.05) (P 0.05); The infiltration density of CD68 positive macrophages in the paracancerous tissues of HCC patients with different AFP and tumor diameter was also different (P 0.05). (3) the expression level of CD206 positive macrophages in different sex and Child-Pugh grading patients was different (P 0.05), and whether there were cirrhosis, different serum total bilirubin and TNM (TU) (TU 0.05). Mor-nodes-metastasis) the expression intensity of the para cancerous tissue in the staging patients was also different (P 0.05). (2) the ROC curve showed that the critical value of CD68 (cut-off value) was set to 71 / each high field (high-power fields, HPF), and the area under the curve (area under curve) was 52.2%, and the sensitivity was 70.7%, The diagnosis of HCC was significant (P=0.003); the best critical value for CD68 was 87 / per high fold field of vision (high-power fields, HPF), AUC was 0.534~0.661, sensitivity 49.5%%, specificity 70.5%, significance for HCC diagnosis (P=0.008). (3) the prognosis of patients with high expression in cancer tissues was poor, and the overall survival rate was poor. The survival time (P=0.014) and the tumor free survival (P=0.003) were shorter than those in the low expression group, while the overall survival time (P=0.020) and the tumor free survival time (P=0.018) of the HCC patients with high expression of CD68 in the para cancer tissues were longer.Cox regression analysis, and the results showed that the high expression of CD68 positive macrophages beside the cancer was the overall prognosis of HCC patients [HR (95%CI) =0.510. P=0.008] and postoperative recurrence of [HR (95%CI) =0.529 (0.299~0.935) and P=0.028] were independent prognostic factors, while the high expression of CD206 positive macrophages in cancer were independent risk factors for the prognosis of HCC patients: the overall survival period [HR (95%CI) =1.792, (1.116~2.879), and tumor free survival period (4) union Analysis of the results of macrophages and HBV of the paracancerous CD68 positive tumor showed that the combination of CD68 positive macrophages or CD206 positive macrophages adjacent to the cancer was analyzed with HBV, and the difference of the tumor free survival time of HCC patients was statistically significant (P 0.05), but the combined analysis of CD68 positive macrophages and HBV had no significant effect on the total survival time (P=0.102). The three part: (1) the levels of serum s CD68 and s CD206 in patients with HCC before and after operation were significantly higher than those in normal control group (P 0.05), but there was no significant difference between preoperative and postoperative serum s CD68 and s CD206 levels, and the difference was not statistically significant (P 0.05). There was a correlation (P 0.05). (2) further analysis found that the two were closely related to the important clinical features of HCC (HBV, cirrhosis, portal hypertension and serum AFP level) (P 0.05). (3) there was no significant difference in the levels of CD68 rs9901675, CD68 rs9901673 and CD206 rs941 three loci. (4) the results of ROC curve analysis showed that the maximum subcurvilinear area was obtained when the serum s CD206 was 20.52ng/ml before operation. The preoperative serum s CD206 had the diagnostic value of HCC (P=0.032), while the preoperative serum s CD68 was not statistically significant (P=0.174). (5) the survival analysis showed that the postoperative serum high expression s, with the portal vein tumor thrombus, and the pre operation white eggs The total bilirubin increased, the total bilirubin increased, the total survival time of HCC patients with lymph node metastasis or distant metastasis was shorter, and the difference was statistically significant (P 0.05). Further Cox regression analysis showed that high expression of s CD68 after operation was [HR (95%CI) =8.059 (1.007~64.487), P=0.049]., the risk factor for independent prognosis. The prognosis of preoperative s CD68, s CD206 and postoperative s CD206 was not statistically significant (P 0.05). Conclusion 1.CD68 rs9901675 polymorphism is related to the genetic susceptibility to HCC disease, and the allele and genotype of this loci may be the risk factors for the onset of recurrence. Sex and CD206 positive macrophages can provide clues for postoperatively stratified management of HCC patients and provide a new way to train macrophages in HCC microenvironment. High expressed CD68 is an independent prognostic factor for HCC patients, and the high expression of CD206 in cancer is an independent risk factor for prognosis in HCC patients. Combined analysis of CD68 or CD206 positive swelling is combined. The tumor macrophage and HBV infection may further improve the predictive ability of recurrence after HCC.3. detection of the serum s CD68 and s CD206 levels in HCC patients can help to observe the immune state. The serum s CD206 level can be used as a potential marker for the early diagnosis of HCC patients. The clinical diagnosis and prognosis evaluation of patients has important clinical value.

【學(xué)位授予單位】：安徽醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R735.7

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